STAT3 inhibitors

ABSTRACT

Compounds as STAT3 inhibitors are described. A pharmaceutical composition comprising the same, methods of making the same, and a method for treating or preventing conditions such as cancer, chronic inflammation, and fibrosis using the same, are described.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is the U.S. National Phase entry of InternationalApplication No. PCT/US2019/028135, filed on Apr. 18, 2019, which claimsthe benefit of and priority to U.S. Provisional Application No.62/659,872, filed on Apr. 19, 2018, and U.S. Provisional Application No.62/793,491, filed on Jan. 17, 2019, the contents of each are herebyincorporated by reference in their entirety.

INCORPORATION BY REFERENCE

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety in order to morefully describe the state of the art as known to those skilled therein asof the date of the invention described herein.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical science.More particularly, the invention relates to compounds and compositionsuseful as pharmaceuticals for inhibiting STAT3. More specifically, theinvention relates to compounds and their use in methods for treatingconditions such as cancer, chronic inflammation, and fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an IR spectrum of the Compound of Formula III.

BACKGROUND

Signal transducer and activator of transcription 3 (STAT3) is one ofseven members of the STAT protein family, which are signalingintermediates that mediate the actions of many cytokines and growthfactors. In addition, STAT3 is an oncogene. See Bromberg, J. F., et al.,STAT3 as an oncogene, CELL, 1998, 295-303; published erratum appears inCELL, 1999 Oct. 15, 1999(2), 239. STAT3 is constitutively active in manydifferent cancers including prostate, breast, lung, squamous cellcarcinoma of the head and neck, multiple myeloma, colon cancer,hepatocellular carcinomas, and large granular lymphocytic leukemia.Furthermore, human tumor xenograft studies in mice have repeatedlydemonstrated that targeting STAT3 either genetically orpharmacologically results in decreased tumor growth and improved animalsurvival by inducing apoptosis in tumor cells, inhibiting angiogenesis,and enhancing anti-tumor immune-mediated cytotoxicity. See, e.g.,Redell, M. S., et al., Targeting transcription factors in cancer:Challenges and evolving strategies, DRUG DISCOVERY TODAY, TECHNOLOGIES,2006 3(3): 261-267; Kato, T., et al., Proteolytic Conversion of STAT3[alpha] to STAT3 [gamma] in Human Neutrophils: Role of Granule derivedSerine Proteases, J. BIOL. CHEM., 2004, 279(30): 31076-31080; Dunn, G.P., et al., Cancer immunoediting: from immunosurveillance to tumorescape, N AT. IMMUNOL., 2002, 3(11): 991-998. Thus, STAT3 has beenidentified as a potential target for drug development to treat cancers.

Muscle wasting is a debilitating complication of catabolic conditionsincluding chronic kidney disease (CKD), diabetes, cancer, or seriousinfections. In mice with CKD, inhibition of myostatin reducedcirculating levels of IL-6 and TNFα, suggesting a link betweeninflammation and muscle wasting as reported in clinical studies. SeeCarrero, J. J., et al., Muscle atrophy, inflammation and clinicaloutcome in incident and prevalent dialysis patients, CLIN. NUTR., 2008,27, 557-564. STAT3 was found to be activated by the IL-6 family ofcytokines, thus suggesting that the STAT3 pathway could be linked toloss of muscle mass. See Hirano, T., et al., Signaling mechanismsthrough gp 130: a model of the cytokine system, CYTOKINE GROWTH FACTORREV., 1997, 8, 241-252.

Fibrosis is a pathological process involving the accumulation ofexcessive extra-cellular matrix in tissues, leading to tissue damage andorgan dysfunction, which can progress to organ failure and death. Insystemic sclerosis, an idiopathic fibrosis disease, the trigger ispostulated to be an autoimmune response that leads to tissue injury,production of growth factors, pro-inflammatory and pro-fibroticcytokines, and accumulation of myofibroblasts. Two potential sources ofmyofibroblasts are the differentiation of local fibroblasts and theprocess of epithelial-to-mesenchymal transition (EMT). IL-6 is aproinflammatory and profibrotic cytokine increasingly recognized as animportant mediator of fibrosis that may contribute to the accumulationof myofibroblasts. After engaging its receptor, IL-6 signals through theSTAT3. Thus, STAT3 represents a potentially important protein to targetto treat fibrosis.

Asthma

Asthma affects 10% of the population worldwide and its prevalence hasbeen increasing over the last decade. See Akinbami L J, Moorman J E,Bailey C, Zahran H S, King M, Johnson C A, et al., Trends in asthmaprevalence, health care use, and mortality in the United States,2001-e2010, NCHS DATA BRIEF, NO 94, HYATTSVILLE, MD: NATIONAL CENTER FORHEALTH STATISTICS, 2012. Asthma is a heterogeneous disease with multiplevariants, the most widely recognized of which is the Th2-phenotype,characterized by atopy, eosinophilia, and responsiveness to steroids.See, e.g., Fahy J. V., Eosinophilic and neutrophilic inflammation inasthma: insightsfrom clinical studies, PROC AM THORAC SOC 2009, 6(3)256-9; Wenzel S. E., Asthma: defining of the persistent adultphenotypes, LANCET 2006, 368(9537): 804-13; Lin T, Poon A H, Hamid Q.,Asthma phenotypes and endotypes, CURR OPIN PUML MED. 2013, 19(1):18-23.However, as many as 10% of patients have the Th17-phenotype of asthmawhich is non-atopic, neutrophilic, and steroid-resistant (“Proceedingsof the ATS workshop on refractory asthma: current understanding,recommendations, and unanswered questions,” AM J RESPIR CRIT CARE MED2000; 162(6):2341-51; Al-Ramili W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, et al., T(H)17-associated cytokines (IL-17Aand IL-17F) in severe asthma, J ALLERGY CLIN IMMUNOL 2009;123(5):1185-7; McKinley L, Alcorn J F, Peterson A, Dupont R B, KapadiaS, Logar A, et al., Th17 cells mediate steroid-resistant airwayinflammation and airway hyperresponsiveness in mice, J IMMUNOL 2008;181(6):4089-97); resulting in a higher morbidity and mortality owing tothe lack of available effective treatments. Al-Ramili W, Prefontaine D,Chouiali F, Martin J G, Olivenstein R, Lemiere C, et al.,T(H)17-associated cytokines (IL-17A andIL-17F) in severe asthma, JALLERGY CLIN IMMUNOL 2009, 123(5):1185-7; Newcomb D C, Peebles R S Jr.Th-17 mediated inflammation in asthma, CURR OPIN IMMUNOL 2013;25(6):755-60. Alternative therapeutic options clearly are needed forthis subset of patients.

Signal transducer and activator of transcription 3 (STAT3) is essentialfor Th17 lymphocyte development and cytokine production and itsactivation is linked to the development of airway inflammation. Harris TJ, Grosso J F, Yen H, Xin H, Kortylewski M, Albesiano E, et al., Cuttingedge: an in vivo requirement for STAT3 signaling in Th17 development andTh17-dependent autoimmunity, J IMMUNOL 2007, 179(7):4333-7; Zhou L,Ivanov I I, Spolski R, Min R, Shenderov K, Egawa T, et al., IL-6programs T(H)-17 cell differentiation by promoting sequential engagementof the IL-21 and IL-23 pathways, NAT IMMUNOL 2007, 8(9):967-74. Uponactivation, STAT3 is recruited to cytokine-activated receptor complexesand becomes phosphorylated at Tyr (Y) 705. Phosphotyrosylated (p) STAT3homodimerizes through reciprocal SH2-pY705 interactions, translocates tothe nucleus, and binds to promoters to transcriptionally activate genesthat drive Th17 differentiation and production of multiple cytokines.Sakaguchi M, Oka M, Iwasaki T, Fukami Y, Nishigori C., Role andregulation of STAT3 phosphorylation at Ser727 in melanocytes andmelanoma cells, J INVEST DERMATOL 2012; 132(7):1877-85; Darnell J E Jr.,STATs and gene regulation, SCIENCE 1997, 227(5332):1630-5. STAT3activation also is involved in Th2 cytokine production (Doganci A,Eigenbrod T, Krug N, De Sanctis G T, Hausding M, Erpenbeck V J, et al.,The IL-6R alpha chain controls lung CD4+CD25+ Treg development andfunction during allergic airway inflammation in vivo, J CLIN INVEST2005, 115(2):313-25; Finotto S, Eigenbrod T, Karwot R, Boross I, DoganciA, Ito H, et al., Local blockade of IL-6R signaling induces lung CD4+ Tcell apoptosis in a murine model of asthma via regulatory T cells, INT,IMMUNOL., 2007, 19(6):685-93; Simeone-Penney M C, Svergnini M, Tu P,Homer R J, Mariana T J, Cohn L, et al., Airway epithelial STAT3 isrequired for allergic inflammation in a murine model of asthma, J.IMMUNOL. 2007, 178(10):6191-9; Stritesky G L, Muthukrishnan R, Sehra S,Goswami R, Pham D, Travers J, et al., The transcription factor STAT3 isrequired for T helper 2 cell development, I MMUNITY 2011, 34(1):39-49),making it an attractive target for asthma treatment.

Anaphylaxis

Despite a significant burden of eczematous skin disease and elevationsin both total and allergen-specific serum IgE, clinical food allergy andanaphylaxis are markedly diminished in patients with autosomal dominanthyper-IgE syndrome (AD-HIES) caused by STAT3 mutations. STAT3-silencedmast cells fail to degranulate normally due to a proximal FcεRIsignaling defect. Siegel, A. M. et al. Diminished allergic disease inpatients with STAT3 mutations reveals a role for STAT3 signaling in mastcell degranulation, THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 132,1388-1396, doi:10.1016/j.jaci.2013.08.045 (2013). Given that theSTAT3-dependent cytokine IL-6 can lead to vascular leak (Wei, L. H. etal., The role of IL-6 trans-signaling in vascular leakage: implicationsfor ovarian hyperstimulation syndrome in a murine model, THE JOURNAL OFCLINICAL ENDOCRINOLOGY AND METABOLISM, 98, E472-484,doi:10.1210/jc.2012-3462 (2013)) and STAT3 signaling is involved in gapjunction dynamics (Guy, S., Geletu, M., Arulanandam, R. & Raptis, L.,Stat3 and gap junctions in normal and lung cancer cells , CANCERS 6,646-662, doi:10.3390/cancers6020646 (2014)), impaired STAT3 function mayalso protect against endothelial permeability during anaphylaxis.Histamine-induced anaphylaxis was blunted in STAT3 mutant AD-HIES miceand in wild-type mice subjected to small molecule STAT3 inhibition.Likewise, histamine skin prick responses were diminished in AD-HIESpatients. Human umbilical vein vascular endothelial cells (HUVECs)derived from patients with AD-HIES or treated with a STAT3 inhibitorfailed to properly signal through Src or to downregulate adherensjunction proteins vascular endothelial (VE)-Cadherin and β-catenin.Diminished STAT3-target mir17-92 expression in AD-HIES HUVECS wasassociated with increases in PTEN—which inhibits Src, and E2F1—whichregulates β-catenin cellular dynamics. Thus, STAT3-dependenttranscriptional activity regulates critical components for thearchitecture and functional dynamics of endothelial junctions andpermeability. Long-term functional ablation of STAT3 prevents vascularmediator-induced dissolution of adherens junctions, and suggests thatclinical conditions of excess vascular permeability, such asanaphylaxis, can be modulated via small molecule inhibition of STAT3.

Following mast cell degranulation, mediators such as histamine, plateletactivating factor (PAF), and thrombin act on target vascular endotheliumto increase nitric oxide synthesis (Palmer, R. M., Ferrige, A. G. &Moncada, S., Nitric oxide release accounts for the biological activityof endothelium-derived relaxing factor, NATURE 327, 524-526,doi:10.1038/327524a0 (1987)), intracellular calcium release (Valone, F.H. & Johnson, B., Modulation of platelet-activating-factor-inducedcalcium influx and intracellular calcium release in platelets by phorbolesters, THE BIOCHEMICAL JOURNAL, 247, 669-674 (1987); Kotlikoff, M. I.,Murray, R. K. & Reynolds, E. E., Histamine-induced calcium release andphorbol antagonism in cultured airway smooth muscle cells, THE AMERICANJOURNAL OF PHYSIOLOGY 253, C561-566 (1987)), and vascular leak,resulting in symptoms of immediate hypersensitivity (Kaliner, M.,Sigler, R., Summers, R. & Shelhamer, J. H., Effects of infusedhistamine: analysis of the effects of H-1 and H-2 histamine receptorantagonists on cardiovascular and pulmonary responses, THE JOURNAL OFALLERGY AND CLINICAL IMMUNOLOGY, 68, 365-371 (1981); Kirsch, C. M.,Brokaw, J. J., Prow, D. M. & White, G. W., Mechanism of plateletactivating factor-induced vascular leakage in the rat trachea,EXPERIMENTAL LUNG RESEARCH, 18, 447-459 (1992)). Endothelial adherensjunctions regulate vascular leak and are formed by VE-cadherin linked byits cytoplasmic tail to intracellular anchors such as alpha-catenin,β-catenin, and plakoglobin (Andriopoulou, P., Navarro, P., Zanetti, A.,Lampugnani, M. G. & Dejana, E., Histamine induces tyrosinephosphorylation of endothelial cell-to-cell adherens junctions,ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, 19, 2286-2297(1999)). Vascular permeability can be achieved by uncoupling VE-cadherinfrom β-catenin via a Src/Yes kinase-dependent mechanism (Wallez, Y. etal., Src kinase phosphorylates vascular endothelial-cadherin in responseto vascular endothelial growth factor: identification of tyrosine 685 asthe unique target site, ONCOGENE 26, 1067-1077,doi:10.1038/sj.onc.1209855 (2007); Weis, S., Cui, J., Barnes, L. &Cheresh, D., Endothelial barrier disruption by VEGF-mediated Srcactivity potentiates tumor cell extravasation and metastasis, THEJOURNAL OF CELL BIOLOGY 167, 223-229, doi:10.1083/jcb.200408130 (2004)).

STAT3 signaling has been implicated in gap junction intercellularcommunication, IL-6- and IL11-induced vascular leakage, down-regulationof VE-cadherin concomitant with phosphorylation of STAT3, and theSTAT3/mir17-92/E2F1 dependent regulation of β-catenin nucleartranslocation and transcriptional activity. See, e.g., Wei, L. H. etal., The role of IL-6 trans-signaling in vascular leakage: implicationsfor ovarian hyperstimulation syndrome in a murine model, THE JOURNAL OFCLINICAL ENDOCRINOLOGY AND METABOLISM 98, E472-484,doi:10.1210/jc.2012-3462 (2013); Guy, S., Geletu, M., Arulanandam, R. &Raptis, L., Stat3 and gap junctions in normal and lung cancer cells,CANCERS 6, 646-662, doi:10.3390/cancers6020646 (2014);Snyder-Talkington, B. N., Schwegler-Berry, D., Castranova, V., Qian, Y.& Guo, N. L., Multi-walled carbon nanotubes induce human microvascularendothelial cellular effects in an alveolar-capillary co-culture withsmall airway epithelial cells, PARTICLE AND FIBRE TOXICOLOGY 10, 35,doi:10.1186/1743-8977-10-35 (2013); Dai, B. et al., STAT3 mediatesresistance to MEK inhibitor through microRNA miR-17, CANCER RESEARCH 71,3658-3668, doi:10.1158/0008-5472.CAN-10-3647 (2011); van Haaften, G. &Agami, R., Tumorigenicity of the miR-17-92 cluster distilled, GENES &DEVELOPMENT 24, 1-4, doi:10.1101/gad.1887110 (2010); Kawada, M. et al.,Signal transducers and activators of transcription 3 activation isinvolved in nuclear accumulation of beta-catenin in colorectal cancer,CANCER RESEARCH 66, 2913-2917, doi:10.1158/0008-5472.CAN-05-3460 (2006);Mahboubi, K., Biedermann, B. C., Carroll, J. M. & Pober, J. S., IL-11activates human endothelial cells to resist immune-mediated injury,JOURNAL OF IMMUNOLOGY 164, 3837-3846 (2000). Thus, STAT3 inhibitionwould be anticipated to reduce vascular permeability in the setting ofanaphylaxis.

Inflammatory Bowel Disease (IBD)

IBD presents as either ulcerative colitis (UC) or Crohn's disease (CD).The etiology of UC and CD are not established, although several geneshave been implicated as risk factors for IBD in genome-wide associationstudies (GWAS), including ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15,JAK2, STAT3, IL23R, and ORMDL3, which implicate antimicrobial peptides,innate and adaptive immune cell function, Th17 cells, regulatory T cells(Tregs), and cytokines (tumor necrosis factor, interleukins 17, 23, 12,22, and IL-6). Many of these cytokines serve as ligands for cell surfacereceptors that activate STAT3. STAT3 within three cell lineages-myeloidcells, enterocytes, and T cells—has been demonstrated to contribute tocolitis in mice and humans (Takeda K, Clausen B E, Kaisho T, et al.,Enhanced Th1 activity and development of chronic enterocolitis in micedevoid of Stat3 in macrophages and neutrophils, IMMUNITY 1999, 10:39-49;Atreya R, Mudter J, Finotto S, et al., Blockade ofinterleukin 6 transsignaling suppresses T-cell resistance against apoptosis in chronicintestinal inflammation: evidence in crohn disease and experimentalcolitis in vivo, NAT MED 2000, 6:583-8; Suzuki A, Hanada T, Mitsuyama K,et al., CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3activation and intestinal inflammation, J. EXP. MED. 2001, 193:471-81),but with contrasting effects. On the one hand, genetic deletion of STAT3within myeloid cells (neutrophils and macrophages) or enterocytesresulted in chronic murine colitis or rendered mice more susceptible toexperimental colitis, respectively. Pickert G, Neufert C, Leppkes M, etal., STAT3 links IL-22 signaling in intestinal epithelial cells tomucosal wound healing, THE JOURNAL OF EXPERIMENTAL MEDICINE, 2009,206:1465-72. Thus, STAT3 within myeloid cells and enterocytes appears toprotect against colitis. On the other hand, more recent studies in micedemonstrated that STAT3 within infiltrating CD4⁺ T cells prevents theirapoptosis, which contributes to chronic intestinal inflammation(reviewed in Atreya R, Neurath M F, Signaling molecules: the pathogenicrole of the IL-6/STAT-3 trans signaling pathway in intestinalinflammation and in colonic cancer, CURR DRUG TARGETS 2008, 9:369-74)indicating that STAT3 activation within T cells is necessary for chroniccolitis.

Results from our studies examining the effects of modulating STAT3activity either genetically or pharmacologically in two mouse models ofIBD—dextran sodium salt (DSS; UC model) and trinitrobenzoic acid (TNBS;CD model) indicate the net effect of STAT3 across all cells and tissuesis to promote the development of IBD. In addition to our findings inmice, other groups have shown that levels of activated STAT3 (pY-STAT3)were directly correlated with extent of inflammation in intestinaltissues from humans with IBD. Musso A, Dentelli P, Carlino A, et al.,Signal transducers and activators of transcription 3 signaling pathway:an essential mediator of inflammatory bowel disease and other forms ofintestinal inflammation, INFLAMM BOWEL DIS., 2005, 11:91-8; Mudter J,Weigmann B, Bartsch B, et al., Activation pattern of signal transducersand activators of transcription (STAT) factors in inflammatory boweldiseases, AM J GASTROENTEROL, 2005, 100:64-72; Mitsuyama K, Matsumoto S,Masuda J, et al., Therapeutic strategies for targeting the IL-6/STAT3cytokine signaling pathway in inflammatory bowel disease, ANTICANCERRESEARCH 2007, 27:3749-56. Thus, targeting STAT3 may represent aneffective means of treating IBD patients refractory to current standardsof care.

Therefore, there remains a need to develop novel compounds and methodsfor modulating or inhibiting STAT3 activities.

SUMMARY OF THE INVENTION

In one aspect, compounds or pharmaceutically acceptable salts thereofuseful as STAT3 modulators or inhibitors having the structure of FormulaI are described herein,

where the various substituents are defined in one or more embodimentsherein. The compounds described herein modulate (e.g., inhibit) STAT3and thus can be useful as treatment of one or more of the disordersdescribed herein. Methods for synthesizing these compounds are alsodescribed herein. Compositions and methods described herein are usefulfor inhibiting STAT3 in vitro and in vivo. Such compositions and methodsthus are useful in a number of clinical applications, including aspharmaceutical agents and methods for treating disorders or conditionsinvolving unwanted STAT3 activities. Non-limiting examples of thedisorders include anaphylaxis, muscle wasting, muscle weakness,cachexia, asthma, ulcerative colitis, non-alcoholic fatty liver disease,fibrosis, steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, amyloidosis,astrogliosis due to Alzheimer's or other neurodegenerative disease, anda combination thereof.

In one aspect, a compound of Formula I,

or a pharmaceutically acceptable salt thereof is described, where

-   -   each occurrence of R₁ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or        optionally substituted heterocycle;    -   n₁ is 0, 1, 2, 3, or 4;    -   each occurrence of R₂ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted        aryl, optionally substituted aryloxyl, or optionally substituted        heterocycle;    -   n₂ is 0, 1, 2, 3, 4, or 5;    -   R₃ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), OC(═O)R_(a), alkyl, alkenyl, cycloalkyl, or optionally        substituted aryl or heteroaryl;    -   R₄ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), NR_(b)R_(c), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl;    -   each occurrence of R₅, R₆, and R₇ is independently hydrogen,        halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₃ is 0, 1, 2, 3, or 4; and    -   each occurrence of R_(a), R_(b), and R_(c) is independently        hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,        heterocycle, or aryl; or said R_(b) and R_(c) together with the        nitrogen atom to which they are bonded optionally form a        heterocycle comprising 1-4 heteroatoms.

In any one or more of the embodiments described herein, each occurrenceof R₁ is independently hydrogen, halogen, cyano, nitro, CF₃, OCF₃,OR_(a), or SR_(a).

In any one or more of the embodiments described herein, each occurrenceof R₁ is independently C(═O)R_(a), OC(═O)R_(a), C(═O)OR_(a),NR_(a)R_(b), NR_(b)C(═O)R_(a), C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a),OC(═O)NR_(b)R_(c), or NR_(a)C(═O)NR_(b)R_(c).

In any one or more of the embodiments described herein, each occurrenceof R₁ is independently alkyl, alkenyl, cycloalkyl, optionallysubstituted aryl, or optionally substituted heterocycle.

In any one or more of the embodiments described herein, R₁ is H.

In any one or more of the embodiments described herein, n₁ is 0, 1, or2.

In any one or more of the embodiments described herein, n₁ is 1.

In any one or more of the embodiments described herein, n₁ is 0.

In any one or more of the embodiments described herein, each occurrenceof R₂ is independently hydrogen, halogen, cyano, nitro, CF₃, OCF₃,OR_(a), or SR_(a).

In any one or more of the embodiments described herein, each occurrenceof R₂ is independently C(═O)R_(a), OC(═O)R_(a), C(═O)OR_(a),NR_(a)R_(b), NR_(b)C(═O)R_(a), C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a),OC(═O)NR_(b)R_(c), or NR_(a)C(═O)NR_(b)R_(c).

In any one or more of the embodiments described herein, each occurrenceof R₂ is independently alkyl, alkenyl, cycloalkyl, optionallysubstituted aryl, or optionally substituted heterocycle.

In any one or more of the embodiments described herein, R₂ is H.

In any one or more of the embodiments described herein, n₂ is 0, 1, or2.

In any one or more of the embodiments described herein, n₂ is 1.

In any one or more of the embodiments described herein, n₂ is 0.

In any one or more of the embodiments described herein, R₃ is hydrogen,halogen, cyano, nitro, or CF₃.

In any one or more of the embodiments described herein, R₃ is OCF₃,OR_(a), SR_(a), or OC(═O)R_(a).

In any one or more of the embodiments described herein, R₃ is alkyl,alkenyl, or cycloalkyl.

In any one or more of the embodiments described herein, R₃ is H.

In any one or more of the embodiments described herein, R₄ is hydrogen,halogen, cyano, nitro, or OR_(a).

In any one or more of the embodiments described herein, R₄ is OCF₃,SR_(a), or OC(═O)R_(a).

In any one or more of the embodiments described herein, R₄ is alkyl,alkenyl, or cycloalkyl.

In any one or more of the embodiments described herein, R₄ is OH.

In any one or more of the embodiments described herein, R₄ is OMe.

In any one or more of the embodiments described herein, R₅, R₆, and R₇are each independently selected from the group consisting of hydrogen,halogen, cyano, nitro, and CF₃.

In any one or more of the embodiments described herein, R₅, R₆, and R₇are each independently selected from the group consisting of OCF₃,OR_(a), and SR_(a).

In any one or more of the embodiments described herein, R₅, R₆, and R₇are each independently selected from the group consisting of OCF₃ andOR_(a).

In any one or more of the embodiments described herein, R₅, R₆, and R₇are each independently selected from the group consisting of C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b), NR_(b)C(═O)R_(a),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a), OC(═O)NR_(b)R_(c), andNR_(a)C(═O)NR_(b)R_(c).

In any one or more of the embodiments described herein, R₅, R₆, and R₇are each independently selected from the group consisting of alkyl,alkenyl, cycloalkyl, optionally substituted aryl, and optionallysubstituted heterocycle.

In any one or more of the embodiments described herein, each occurrenceof R₅, R₆, and R₇ is H.

In any one or more of the embodiments described herein, n₃ is 0, 1, or2.

In any one or more of the embodiments described herein, n₃ is 1.

In any one or more of the embodiments described herein, n₃ is 0.

In any one or more of the embodiments described herein, each occurrenceof R_(a) is independently hydrogen, alkyl, heterocycle, or aryl.

In any one or more of the embodiments described herein, each occurrenceof R_(a) is independently hydrogen or alkyl.

In any one or more of the embodiments described herein, each occurrenceof R_(b) and Re is independently hydrogen, alkyl, heterocycle, or aryl.

In any one or more of the embodiments described herein, each occurrenceof R_(b) and Re is independently hydrogen or alkyl.

In any one or more of the embodiments described herein, R_(b) and R_(c)together with the nitrogen atom to which they are bonded optionally forma heterocycle comprising 1-4 heteroatoms each selected from the groupconsisting of N, O, and S.

In any one or more of the embodiments described herein, the compound ofclaim 1 has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In any one or more of the embodiments described herein, R₂ is H, OH,alkyl, alkoxy, halogen, NR_(b)R_(c), CF₃, OCF₃, or CN.

In any one or more of the embodiments described herein, R₂ is NH₂, OH,OMe, OEt, OCH₂CH₂CH₃, or OCH(CH₃)₂.

In any one or more of the embodiments described herein, R₂ is selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl,tert-butyl, F, Cl, Br, CF₃, nitro, methoxy, ethoxy, OCF₃, —C(═O)Me,—C(═O)OMe, —NHC(═O)Me, 1,4-dioxanyl, cyclohexanyl, cyclohexenyl,phenoxy, 2-methoxyphenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy,2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 2-methylphenoxy,3-methylphenoxy, and 4-methylphenoxy.

In any one or more of the embodiments described herein, R₂ is OMe.

In any one or more of the embodiments described herein, R₃ is H, OH,alkyl, alkoxy, or halogen.

In any one or more of the embodiments described herein, R₃ is H.

In any one or more of the embodiments described herein, R₄ is H, alkyl,OH, NH₂, alkoxy, halogen, CF₃, or CN.

In any one or more of the embodiments described herein, R₄ is H, OH, oralkoxy.

In any one or more of the embodiments described herein, R₄ is OH.

In any one or more of the embodiments described herein, R₄ is OMe.

In any one or more of the embodiments described herein, the compound hasthe structure of Formula III,

or a pharmaceutically-acceptable salt thereof.

In any one or more of the embodiments described herein, the compound isselected from the group consisting of the compounds in Table 1a, or apharmaceutically acceptable salt thereof.

In any one or more of the embodiments described herein, the compound isselected from the group consisting of the compounds in Table 1b, or apharmaceutically-acceptable salt thereof.

In another aspect, a pharmaceutical composition is described, includingat least one compound according to any one of the embodiments disclosedherein, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

In yet another aspect, a method of inhibiting STAT3 in a cell isdescribed, including delivering to the cell an effective amount of atleast one compound according to any one of the embodiments disclosedherein or a pharmaceutically acceptable salt thereof.

In any one or more of the embodiments described herein, the cell is invivo in a mammal.

In any one or more of the embodiments described herein, the mammal is ahuman, a dog, a cat, a horse, a cow, a pig, a sheep, or a goat.

In any one or more of the embodiments described herein, the cell is acancer cell.

In any one or more of the embodiments described herein, the methodfurther includes inducing apoptosis in the cancer cell.

In any one or more of the embodiments described herein, the methodfurther includes inhibiting angiogenesis in a tumor, enhancinganti-tumor immune-mediated cytotoxicity, decreasing tumor growth,improving the mammal's survival, inhibiting STAT3 phosphorylation,and/or inhibiting nuclear-to-cytoplasmic translocation of STAT3.

In any one or more of the embodiments described herein, the human issuffering from, or known, suspected, or at risk for developing aneurodegenerative disease, anaphylaxis, muscle wasting, muscle weakness,cachexia, asthma, ulcerative colitis, non-alcoholic fatty liver disease,fibrosis, steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, amyloidosis,astrogliosis in Alzheimer's or other neurodegenerative disease, or acombination thereof.

In any one or more of the embodiments described herein, thehyperproliferative disease is selected from the group consisting of headand neck cancer, lung cancer, liver cancer, breast cancer, skin cancer,kidney cancer, testicular cancer, colon cancer, rectal cancer, gastriccancer, metastatic melanoma, prostate cancer, ovarian cancer, cervicalcancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer,pancreatic cancer, stomach cancer, anal cancer, prostate cancer,multiple myeloma, post-transplant lymphoproliferative disease,restenosis, myelodysplastic syndrome, and leukemia.

In any one or more of the embodiments described herein, the leukemia isacute myelogenous leukemia.

In any one or more of the embodiments described herein, the fibrosis isselected from the group consisting of pulmonary fibrosis, bone marrowfibrosis, intestine fibrosis, pancreas fibrosis, joint fibrosis, liverfibrosis, retroperionteum, myelofibrosis, and dermal fibrosis.

In any one or more of the embodiments described herein, the viralinfection is a chronic viral infection.

In any one or more of the embodiments described herein, the chronicviral infection is AIDS, HIV infection, Hepatitis B virus infection,Hepatitis C virus infection, or Epstein-Barr virus infection.

In any one or more of the embodiments described herein, the disorder isasthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration oramyloidosis.

In any one or more of the embodiments described herein, the anaphylaxiscomprises anaphylactic shock.

In any one or more of the embodiments described herein, the disorder isselected from the group consisting of muscle wasting, muscle weakness,cachexia, and a combination thereof; and the human has or is at risk ofhaving muscle wasting, cachexia, renal failure, cancer, AIDS, HIVinfection, chronic obstructive lung disease (including emphysema),multiple sclerosis, congestive heart failure, tuberculosis, familialamyloid polyneuropathy, acrodynia, hormonal deficiency, metabolicacidosis, infectious disease, chronic pancreatitis, autoimmune disorder,celiac disease, Crohn's disease, electrolyte imbalance, Addison'sdisease, sepsis, burns, trauma, fever, long bone fracture,hyperthyroidism, prolonged steroid therapy, surgery, bone marrowtransplant, atypical pneumonia, brucellosis, endocarditis, Hepatitis B,lung abscess, mastocytosis, paraneoplastic syndrome, polyarteritisnodosa, sarcoidosis, systemic lupus erythematosus, visceralleishmaniasis, prolonged bed rest, or drug addiction.

In any one or more of the embodiments described herein, the chronicobstructive lung disease is emphysema.

In any one or more of the embodiments described herein, theneurodegenerative disease is chemotherapy-induced peripheral neuropathy,diabetic neuropathy or chemobrain.

In yet another aspect, a method of treating or preventing a disorder ina mammalian species in need thereof is described, includingadministering to the mammalian species a therapeutically effectiveamount of at least one compound according to any one of the embodimentsdisclosed herein or a pharmaceutically acceptable salt thereof, whereinthe disorder is selected from the group consisting of aneurodegenerative disease, anaphylaxis, muscle wasting, muscle weakness,cachexia, asthma, ulcerative colitis, non-alcoholic fatty liver disease,fibrosis, steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, amyloidosis,astrogliosis in Alzheimer's or other neurodegenerative disease, and acombination thereof.

In any one or more of the embodiments described herein, the mammalianspecies is a human, a dog, a cat, a horse, a cow, a pig, a sheep, or agoat.

In any one or more of the embodiments described herein, the mammalianspecies is a human.

In any one or more of the embodiments described herein, the human issuffering from, at risk of having, or susceptible to have the disorder.

In any one or more of the embodiments described herein, thehyperproliferative disease is selected from the group consisting of headand neck cancer, lung cancer, liver cancer, breast cancer, skin cancer,kidney cancer, testicular cancer, colon cancer, rectal cancer, gastriccancer, metastatic melanoma, prostate cancer, ovarian cancer, cervicalcancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer,pancreatic cancer, stomach cancer, anal cancer, prostate cancer,multiple myeloma, post-transplant lymphoproliferative disease,restenosis, myelodysplastic syndrome, and leukemia.

In any one or more of the embodiments described herein, the leukemia isacute myelogenous leukemia.

In any one or more of the embodiments described herein, the fibrosis isselected from the group consisting of pulmonary fibrosis, bone marrowfibrosis, intestinal fibrosis, pancreatic fibrosis, joint fibrosis,liver fibrosis, retroperionteum, myelofibrosis, and dermal fibrosis.

In any one or more of the embodiments described herein, the viralinfection is a chronic viral infection.

In any one or more of the embodiments described herein, the chronicviral infection is AIDS, HIV infection, Hepatitis B virus infection,Hepatitis C virus infection, or Epstein-Barr virus infection.

In any one or more of the embodiments described herein, the disorder isasthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, oramyloidosis.

In any one or more of the embodiments described herein, the anaphylaxiscomprises anaphylactic shock.

In any one or more of the embodiments described herein, the disorder isselected from the group consisting of muscle wasting, muscle weakness,cachexia, and a combination thereof; and the human has or is at risk ofhaving muscle wasting, cachexia, renal failure, cancer, AIDS, HIVinfection, chronic obstructive lung disease (including emphysema),multiple sclerosis, congestive heart failure, tuberculosis, familialamyloid polyneuropathy, acrodynia, hormonal deficiency, metabolicacidosis, infectious disease, chronic pancreatitis, autoimmune disorder,celiac disease, Crohn's disease, electrolyte imbalance, Addison'sdisease, sepsis, burns, trauma, fever, long-bone fracture,hyperthyroidism, prolonged steroid therapy, surgery, bone marrowtransplant, atypical pneumonia, brucellosis, endocarditis, Hepatitis B,lung abscess, mastocytosis, paraneoplastic syndrome, polyarteritisnodosa, sarcoidosis, systemic lupus erythematosus, visceralleishmaniasis, prolonged bed rest, or drug addiction.

In any one or more of the embodiments described herein, the chronicobstructive lung disease is emphysema.

In any one or more of the embodiments described herein, theneurodegenerative disease is chemotherapy-induced peripheral neuropathy,diabetic neuropathy, or chemobrain.

In yet another aspect, a method of making a compound of Formula I isdescribed, including the step of oxidizing a compound of Formula Ix toform the compound of Formula I using an oxidation reagent in step a):

-   -   wherein each occurrence of R₁ is independently hydrogen,        halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₁ is 0, 1, 2, 3, or 4;    -   each occurrence of R₂ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted        aryl, optionally substituted aryloxyl, or optionally substituted        heterocycle;    -   n₂ is 0, 1, 2, 3, 4, or 5;    -   R₃ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), OC(═O)R_(a), alkyl, alkenyl, cycloalkyl, or optionally        substituted aryl or heteroaryl;    -   R₄ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), NR_(b)R_(c), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl;    -   each occurrence of R₅, R₆, and R₇ is independently hydrogen,        halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₃ is 0, 1, 2, 3, or 4; and    -   each occurrence of R_(a), R_(b), and R_(c) is independently        hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,        heterocycle, or aryl; or said R_(b) and R_(c) together with the        nitrogen atom to which they are bonded optionally form a        heterocycle comprising 1-4 heteroatoms.

In any one or more of the embodiments described herein, the oxidationreagent is selected from the group consisting of NaIO₄, H₂O₂, MCPBA, anda combination thereof.

In any one or more of the embodiments described herein, the oxidationreagent is NaIO₄.

In any one or more of the embodiments described herein, NaIO₄ isprepared in situ.

In any one or more of the embodiments described herein, the oxidationreagent is used in the amount of 1.5-4.0 equivalence to the compound ofFormula Ix.

In any one or more of the embodiments described herein, the oxidationreagent is used in the amount of 2.0-3.5 equivalence to the compound ofFormula Ix.

In any one or more of the embodiments described herein, step a) isconducted for 12 hours to 2 days.

In any one or more of the embodiments described herein, step a) isconducted for 1 day.

In any one or more of the embodiments described herein, each occurrenceof R₁ is independently hydrogen, halogen, cyano, nitro, CF₃, OCF₃,OR_(a), or SR_(a).

In any one or more of the embodiments described herein, each occurrenceof R₁ is H.

In any one or more of the embodiments described herein, each occurrenceof R₂ is independently halogen, cyano, nitro, CF₃, OCF₃, OR_(a), orSR_(a).

In any one or more of the embodiments described herein, R₂ is OMe and n₂is 1.

In any one or more of the embodiments described herein, R₃ is OCF₃,OR_(a), SR_(a), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl.

In any one or more of the embodiments described herein, R₃ is H.

In any one or more of the embodiments described herein, the compound ofFormula I has the structure of Formula III,

and the compound of Formula Ix has the structure of Formula IIIx,

Any aspect or embodiment disclosed herein may be combined with anotheraspect or embodiment disclosed herein. The combination of one or moreembodiments described herein with other one or more embodimentsdescribed herein is expressly contemplated.

FURTHER DESCRIPTION OF THE INVENTION Definitions

The following are definitions of terms used in the presentspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification individually or as part of another group, unless otherwiseindicated. Unless otherwise defined, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art.

The terms “alkyl” and “alk” refer to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl,propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl,heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl, dodecyl, and the like. The term “(C1-C4) alkyl” refers to astraight or branched chain alkane (hydrocarbon) radical containing from1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl,t-butyl, and isobutyl. “Substituted alkyl” refers to an alkyl groupsubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include but are not limited to one or more of the followinggroups: hydrogen, halogen (e.g., a single halogen substituent ormultiple halo substituents forming, in the latter case, groups such asCF₃ or an alkyl group bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃,OCF₃, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,OR_(a), SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. In the aforementioned exemplary substituents,groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl,heterocycle, and aryl can themselves be optionally substituted.

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary such groups include ethenyl orallyl. The term “C2-C6 alkenyl” refers to a straight or branched chainhydrocarbon radical containing from 2 to 6 carbon atoms and at least onecarbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl,(E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl,2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl,(E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl,(E)-hex-3-enyl, and (E)-hex-1,3-dienyl. “Substituted alkenyl” refers toan alkenyl group substituted with one or more substituents, preferably 1to 4 substituents, at any available point of attachment. Exemplarysubstituents include but are not limited to one or more of the followinggroups: hydrogen, halogen (e.g., a single halogen substituent ormultiple halo substituents forming, in the latter case, groups such asCF₃ or an alkyl group bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃,OCF₃, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,OR_(a), SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond. Exemplary such groups include ethynyl. The term“C2-C6 alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 6 carbon atoms and at least onecarbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl,but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl,hex-2-ynyl, or hex-3-ynyl. “Substituted alkynyl” refers to an alkynylgroup substituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include but are not limited to one or more of the followinggroups: hydrogen, halogen (e.g., a single halogen substituent ormultiple halo substituents forming, in the latter case, groups such asCF₃ or an alkyl group bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃,OCF₃, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,OR_(a), SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c) and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c), together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted.

The term “cycloalkyl” refers to a fully-saturated cyclic hydrocarbongroup containing from 1 to 4 rings and 3 to 8 carbons per ring. “C3-C7cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl groupsubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include but are not limited to one or more of the followinggroups: hydrogen, halogen (e.g., a single halogen substituent ormultiple halo substituents forming, in the latter case, groups such asCF₃ or an alkyl group bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃,OCF₃, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,OR_(a), SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted. Exemplary substituents also includespiro-attached or fused cyclic substituents, especially spiro-attachedcycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle(excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fusedheterocycle, or fused aryl, where the aforementioned cycloalkyl,cycloalkenyl, heterocycle, and aryl substituents can themselves beoptionally substituted.

The term “cycloalkenyl” refers to a partially unsaturated cyclichydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring.Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl,etc. “Substituted cycloalkenyl” refers to a cycloalkenyl groupsubstituted with one more substituents, preferably 1 to 4 substituents,at any available point of attachment. Exemplary substituents include butare not limited to one or more of the following groups: hydrogen,halogen (e.g., a single halogen substituent or multiple halosubstituents forming, in the latter case, groups such as CF₃ or an alkylgroup bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃, OCF₃,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_(a),SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted. Exemplary substituents also includespiro-attached or fused cyclic substituents, especially spiro-attachedcycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle(excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fusedheterocycle, or fused aryl, where the aforementioned cycloalkyl,cycloalkenyl, heterocycle, and aryl substituents can themselves beoptionally substituted.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 5 aromatic rings, especially monocyclic or bicyclic groups such asphenyl, biphenyl, or naphthyl. Where containing two or more aromaticrings (bicyclic, etc.), the aromatic rings of the aryl group may bejoined at a single point (e.g., biphenyl), or fused (e.g., naphthyl,phenanthrenyl, and the like). “Substituted aryl” refers to an aryl groupsubstituted by one or more substituents, preferably 1 to 3 substituents,at any available point of attachment. Exemplary substituents include butare not limited to one or more of the following groups: hydrogen,halogen (e.g., a single halogen substituent or multiple halosubstituents forming, in the latter case, groups such as CF₃ or an alkylgroup bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃, OCF₃,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_(a),SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted. Exemplary substituents also include fused cyclicgroups, especially fused cycloalkyl, fused cycloalkenyl, fusedheterocycle, or fused aryl, where the aforementioned cycloalkyl,cycloalkenyl, heterocycle, and aryl substituents can themselves beoptionally substituted.

The term “carbocycle” refers to a fully saturated or partially saturatedcyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbonsper ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5aromatic rings, especially monocyclic or bicyclic groups such as phenyl,biphenyl, or naphthyl. The term “carbocycle” encompasses cycloalkyl,cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove. The term“substituted carbocycle” refers to carbocycle or carbocyclic groupssubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, those described above forsubstituted cycloalkyl, substituted cycloalkenyl, substitutedcycloalkynyl, and substituted aryl. Exemplary substituents also includespiro-attached or fused cyclic substituents at any available point orpoints of attachment, especially spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle, and aryl substituents can themselves be optionallysubstituted.

The terms “heterocycle” and “heterocyclic” refer to fully saturated, orpartially or fully unsaturated, including aromatic (i.e., “heteroaryl”)cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 memberedbicyclic, or 8 to 16 membered tricyclic ring systems) which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3,or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.(The term “heteroarylium” refers to a heteroaryl group bearing aquaternary nitrogen atom and thus a positive charge.) The heterocyclicgroup may be attached to the remainder of the molecule at any heteroatomor carbon atom of the ring or ring system. Exemplary monocyclicheterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, and the like. Exemplary bicyclicheterocyclic groups include indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl,2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl,benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl], orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl,tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclicgroups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl,phenanthridinyl, xanthenyl, and the like.

“Substituted heterocycle” and “substituted heterocyclic” (such as“substituted heteroaryl”) refer to heterocycle or heterocyclic groupssubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include but are not limited to one or more of the followinggroups: hydrogen, halogen (e.g., a single halogen substituent ormultiple halo substituents forming, in the latter case, groups such asCF₃ or an alkyl group bearing CCl₃), cyano, nitro, oxo (i.e., ═O), CF₃,OCF₃, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl,OR_(a), SR_(a), S(═O)R_(c), S(═O)₂R_(c), P(═O)₂R_(c), S(═O)₂OR_(c),P(═O)₂OR_(c), NR_(b)R_(c), NR_(b)S(═O)₂R_(c), NR_(b)P(═O)₂R_(c),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(d), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), OC(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), or NR_(b)P(═O)₂R_(c), whereineach occurrence of R_(a) is independently hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence ofR_(b), R_(c), and Rd is independently hydrogen, alkyl, cycloalkyl,heterocycle, aryl, or said R_(b) and R_(c) together with the N to whichthey are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,heterocycle, or aryl. The exemplary substituents can themselves beoptionally substituted. Exemplary substituents also includespiro-attached or fused cyclic substituents at any available point orpoints of attachment, especially spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle, and aryl substituents can themselves be optionallysubstituted.

The term “alkylamino” refers to a group having the structure —NHR′,wherein R′ is hydrogen, alkyl or substituted alkyl, or cycloalkyl orsubstituted cyclolakyl, as defined herein. Examples of alkylamino groupsinclude, but are not limited to, methylamino, ethylamino, n-propylamino,iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino,neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and thelike.

The term “dialkylamino” refers to a group having the structure —NRR′,wherein R and R′ are each independently alkyl or substituted alkyl,cycloalkyl or substituted cycloalkyl, cycloalkenyl or substitutedcyclolalkenyl, aryl or substituted aryl, or heterocylyl or substitutedheterocyclyl, as defined herein. R and R′ may be the same or differentin a dialkyamino moiety. Examples of dialkylamino groups include, butare not limited to, dimethylamino, methyl ethylamino, diethylamino,methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino,di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino,di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino,di(cyclohexyl)amino, and the like. In certain embodiments, R and R′ arelinked to form a cyclic structure. The resulting cyclic structure may bearomatic or nonaromatic. Examples of cyclic diaminoalkyl groups include,but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl,morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.

The terms “halogen” or “halo” refer to chlorine, bromine, fluorine, oriodine.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The compounds of the present invention may form salts which are alsowithin the scope of this invention. Reference to a compound of thepresent invention is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s),” as employed herein,denotes acidic and/or basic salts formed with inorganic and/or organicacids and bases. In addition, when a compound of the present inventioncontains both a basic moiety, such as but not limited to a pyridine orimidazole, and an acidic moiety such as but not limited to a carboxylicacid, zwitterions (“inner salts”) may be formed and are included withinthe term “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolation or purification stepswhich may be employed during preparation. Salts of the compounds of thepresent invention may be formed, for example, by reacting a compounddescribed herein with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

The compounds of the present invention which contain a basic moiety,such as but not limited to an amine or a pyridine or imidazole ring, mayform salts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentane propionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates(e.g., 2-hydroxyethanesulfonates), lactates, maleates,methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates, tartrates,thiocyanates, toluenesulfonates such as tosylates, undecanoates, and thelike.

The compounds of the present invention which contain an acidic moiety,such but not limited to a carboxylic acid, may form salts with a varietyof organic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butylamines, and salts with amino acids such as arginine, lysine, and thelike. Basic nitrogen-containing groups may be quatemized with agentssuch as lower alkyl halides (e.g., methyl, ethyl, propyl, and butylchlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl,diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl,lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkylhalides (e.g., benzyl and phenethyl bromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug” as employed herein denotes acompound that, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound asdescribed herein, or a salt and/or solvate thereof. Solvates of thecompounds of the present invention include, for example, hydrates. Incertain embodiments, the compound as described herein may be a prodrugitself and, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound or asalt and/or solvate thereof having desirable biological activities.

Compounds of the present invention, and salts or solvates thereof, mayexist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers of the present compounds (for example, those which mayexist due to asymmetric carbons on various substituents), includingenantiomeric forms and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention may have the S or R configuration as defined by theInternational Union of Pure and Applied Chemistry (IUPAC) 1974Recommendations. The racemic forms can be resolved by physical methods,such as, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives, or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedfrom the racemates by any suitable method, including without limitation,conventional methods, such as, for example, salt formation with anoptically active acid followed by crystallization.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 90%, for example, equal togreater than 95%, equal to or greater than 99% of the compounds(“substantially pure” compounds), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of the presentinvention are also contemplated herein as part of the present invention.

All configurational isomers of the compounds of the present inventionare contemplated, either in admixture or in pure or substantially pureform. The definition of compounds of the present invention embraces bothcis (Z) and trans (E) alkene isomers, as well as cis and trans isomersof cyclic hydrocarbon or heterocyclic rings.

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in “Organic Chemistry,” Thomas Sorrell, University ScienceBooks, Sausalito (1999), the entire contents of which are incorporatedherein by reference.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

Isomeric mixtures containing any of a variety of isomer ratios may beutilized in accordance with the present invention. For example, whereonly two isomers are combined, mixtures containing 50:50, 60:40, 70:30,80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios areall contemplated by the present invention. Those of ordinary skill inthe art will readily appreciate that analogous ratios are contemplatedfor more complex isomer mixtures.

The present invention also includes isotopically-labeled compounds,which are identical to the compounds disclosed herein, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsof the present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, and chlorine, such as ²H, ³H,¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, or an enantiomer,diastereomer, tautomer, or pharmaceutically acceptable salt or solvatethereof, which contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and hence, may be preferred in some circumstances.Isotopically labeled compounds can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples below, bysubstituting a readily-available isotopically labeled reagent for anon-isotopically labeled reagent.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriate opticallyactive acid or base, followed by resolution of the diastereomers thusformed by fractional crystallization or chromatographic means well knownin the art, and subsequent recovery of the pure enantiomers.

It will be appreciated that the compounds, as described herein, may besubstituted with any number of substituents or functional moieties. Ingeneral, the term “substituted” whether preceded by the term“optionally” or not, and substituents contained in formulas of thisinvention, refer to the replacement of hydrogen radicals in a givenstructure with the radical of a specified substituent. When more thanone position in any given structure may be substituted with more thanone substituent selected from a specified group, the substituent may beeither the same or different at every position. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic, substituents of organiccompounds. For purposes of this invention, heteroatoms such as nitrogenmay have hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. Furthermore, this invention is not intended to be limitedin any manner by the permissible substituents of organic compounds.Combinations of substituents and variables envisioned by this inventionare preferably those that result in the formation of stable compoundsuseful in the treatment, for example, of infectious diseases orproliferative disorders. The term “stable,” as used herein, preferablyrefers to compounds which possess stability sufficient to allowmanufacture and which maintain the integrity of the compound for asufficient period of time to be detected and preferably for a sufficientperiod of time to be useful for the purposes detailed herein.

As used herein, the term inhibitor of STAT3 as used herein refers to oneor more molecules that interfere at least in part with the activity ofSTAT3 to perform one or more activities, including the ability of STAT3to bind to a molecule and/or the ability to be phosphorylated.

As used herein, the term “pharmaceutically acceptable” is employedherein to refer to those compounds, materials, compositions, and/ordosage forms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings and animalswithout excessive toxicity, irritation, allergic response, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

As used herein, the terms “cancer” and equivalently, “tumor” refer to acondition in which abnormally replicating cells of host origin arepresent in a detectable amount in a subject. The cancer can be amalignant or non-malignant cancer. Cancers or tumors include but are notlimited to biliary tract cancer; brain cancer; breast cancer; cervicalcancer; choriocarcinoma; colon cancer; endometrial cancer; esophagealcancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias;lymphomas; liver cancer; lung cancer (e.g., small cell and non-smallcell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreaticcancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas;skin cancer; testicular cancer; and thyroid cancer; as well as othercarcinomas and sarcomas. Cancers can be primary or metastatic.

As used herein, the term “at risk for having cancer” is used herein torefer to patients that have a chance to have cancer because of past,present, or future factors. These factors can include but are notlimited to: patient history, family history, identification of markersof generic or tissue-specific cancer such as BRACA-1 or CEA, age, race,diet, being a smoker, or certain exposures such as chemical or radiationexposure.

As used herein, the term “at risk for having muscle wasting” as usedherein refers to an individual that is at risk for having less thantheir normal level of strength or too little muscle or having loss inmuscle, such as an individual that has an underlying medical conditionwith such a symptom, or is elderly.

As used herein, the term “at risk for having cachexia” is used herein torefer to individuals that have a chance to have cachexia because ofpast, present, or future factors. In particular embodiments, anindividual at risk for having cachexia is one that has an underlyingcondition that is known to cause or be associated with cachexia as atleast one symptom. The condition may or may not be chronic. In someembodiments, an underlying medical condition that is known to havecachexia as at least one symptom includes at least renal failure,cancer, AIDS, HIV infection, chronic obstructive lung disease (includingemphysema), multiple sclerosis, congestive heart failure, tuberculosis,familial amyloid polyneuropathy, acrodynia, hormonal deficiency,metaoblic acidosis, infectious disease, chronic pancreatitis, autoimmunedisorder, celiac disease, Crohn's disease, electrolyte imbalance,Addison's disease, sepsis, burns, trauma, fever, long bone fracture,hyperthyroidism, prolonged steroid therapy, surgery, bone marrowtransplant, atypical pneumonia, brucellosis, endocarditis, Hepatitis B,lung abscess, mastocytosis, paraneoplastic syndrome, polyarteritisnodosa, sarcoidosis, systemic lupus erythematosus, myositis,polymyositis, dematomyosytis, rheumatological diseases, autoimmunedisease, collagen-vascular disease, visceral leishmaniasis, prolongedbed rest, and/or addiction to drugs, such as amphetamine, opiates, orbarbiturates.

As used herein, the term “at risk for having fibrosis” is used herein torefer to individuals that have a chance to have fibrosis because ofpast, present, or future factors.

As used herein, the term “mammal” is an appropriate subject for themethod of the present invention. A mammal may be any member of thehigher vertebrate class Mammalia, including humans; characterized bylive birth, body hair, and mammary glands in the female that secretemilk for feeding the young. Additionally, mammals are characterized bytheir ability to maintain a constant body temperature despite changingclimatic conditions. Examples of mammals are humans, cats, dogs, cows,mice, rats, and chimpanzees. Mammals may be referred to as “patients” or“subjects” or “individuals.”

As used herein, “effective amount” refers to any amount that isnecessary or sufficient for achieving or promoting a desired outcome. Insome instances, an effective amount is a therapeutically effectiveamount. A therapeutically effective amount is any amount that isnecessary or sufficient for promoting or achieving a desired biologicalresponse in a subject. The effective amount for any particularapplication can vary depending on such factors as the disease orcondition being treated, the particular agent being administered, thesize of the subject, or the severity of the disease or condition. One ofordinary skill in the art can empirically determine the effective amountof a particular agent without necessitating undue experimentation.

Compounds

In one aspect, a compound of Formula I,

or a pharmaceutically acceptable salt thereof is described, wherein

-   -   each occurrence of R₁ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or        optionally substituted heterocycle;    -   n₁ is 0, 1, 2, 3, or 4;    -   each occurrence of R₂ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted        aryl, optionally substituted aryloxyl, or optionally substituted        heterocycle;    -   n₂ is 0, 1, 2, 3, 4, or 5;    -   R₃ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), OC(═O)R_(a), alkyl, alkenyl, cycloalkyl, or optionally        substituted aryl or heteroaryl;    -   R₄ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), NR_(b)R_(c), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl;    -   each occurrence of R₅, R₆, and R₇ is independently hydrogen,        halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₃ is 0, 1, 2, 3, or 4; and    -   each occurrence of R_(a), R_(b), and R_(c) is independently        hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,        heterocycle, or aryl; or said R_(b) and R_(c) together with the        nitrogen atom to which they are bonded optionally form a        heterocycle comprising 1-4 heteroatoms.

In some embodiments, each occurrence of R₁ is independently hydrogen,halogen, cyano, nitro, CF₃, OCF₃, OR_(a), or SR_(a). In someembodiments, each occurrence of R₁ is independently C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b), NR_(b)C(═O)R_(a),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a), OC(═O)NR_(b)R_(c), orNR_(a)C(═O)NR_(b)R_(c). In some embodiments, each occurrence of R₁ isindependently alkyl, alkenyl, cycloalkyl, optionally substituted aryl,or optionally substituted heterocycle. In some embodiments, R₁ is H, Me,Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₁ is H, OH, SH, NH₂,CF₃, or OCF₃. In some embodiments, R₁ is H.

In some embodiments, n₁ is 0, 1, or 2. In some embodiments, n₁ is 1. Insome embodiments, n₁ is 0. In some particular embodiments, R₁ is H andn₁ is 0.

In some embodiments, each occurrence of R₂ is independently hydrogen,halogen, cyano, nitro, CF₃, OCF₃, OR_(a), or SR_(a). In someembodiments, each occurrence of R₂ is independently C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b), NR_(b)C(═O)R_(a),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a), OC(═O)NR_(b)R_(c), orNR_(a)C(═O)NR_(b)R_(c). In some embodiments, each occurrence of R₂ isindependently alkyl, alkenyl, cycloalkyl, optionally substituted aryl,or optionally substituted heterocycle. In some embodiments, R₂ is H, Me,Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₂ is H, OH, SH, NH₂,CF₃, or OCF₃. In some embodiments, R₂ is H.

In some embodiments, R₁ and R₂ are both H.

In some embodiments, n₂ is 0, 1, or 2. In some embodiments, n₂ is 1. Insome embodiments, n₂ is 0. In some particular embodiments, R₂ is H andn₂ is 0.

In some embodiments, R₃ is hydrogen, halogen, cyano, nitro, or CF₃. Insome embodiments, R₃ is OCF₃, OR_(a), SR_(a), or OC(═O)R_(a). In someembodiments, R₃ is alkyl, alkenyl, or cycloalkyl. In some embodiments,R₁ is H, Me, Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₃ is H.

In some embodiments, R₄ is hydrogen, halogen, cyano, nitro, or OR_(a).In some embodiments, R₄ is OCF₃, SR_(a), or OC(═O)R_(a). In someembodiments, R₄ is alkyl, alkenyl, or cycloalkyl. In some embodiments,R₄ is H, Me, Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₂ is H,OH, SH, NH₂, CF₃, or OCF₃. In some embodiments, R₄ is OH.

In some embodiments, R₅ is selected from the group consisting ofhydrogen, halogen, cyano, nitro, and CF₃. In some embodiments, R₅ isselected from the group consisting of OCF₃, OR_(a), and SR_(a). In someembodiments, R₅ is selected from the group consisting of C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b), NR_(b)C(═O)R_(a),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a), OC(═O)NR_(b)R_(c), andNR_(a)C(═O)NR_(b)R_(c). In some embodiments, R₅ is selected from thegroup consisting of alkyl, alkenyl, cycloalkyl, optionally substitutedaryl, and optionally substituted heterocycle. In some embodiments, R₅ isH, Me, Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₅ is H, OH, SH,NH₂, CF₃, or OCF₃. In some embodiments, R₅ is H.

In some embodiments, R₆ is selected from the group consisting ofhydrogen, halogen, cyano, nitro, and CF₃. In some embodiments, R₆ isselected from the group consisting of OCF₃, OR_(a), and SR_(a). In someembodiments, R₆ is selected from the group consisting of C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b), NR_(b)C(═O)R_(a),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a), OC(═O)NR_(b)R_(c), andNR_(a)C(═O)NR_(b)R_(c). In some embodiments, R₆ is selected from thegroup consisting of alkyl, alkenyl, cycloalkyl, optionally substitutedaryl, and optionally substituted heterocycle. In some embodiments, R₆ isH, Me, Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments, R₆ is H, OH, SH,NH₂, CF₃, or OCF₃. In some embodiments, R₆ is H.

In some embodiments, each occurrence of R₇ is independently selectedfrom the group consisting of hydrogen, halogen, cyano, nitro, and CF₃.In some embodiments, each occurrence of R₇ is independently selectedfrom the group consisting of OCF₃, OR_(a), and SR_(a). In someembodiments, each occurrence of R₇ is independently selected from thegroup consisting of C(═O)R_(a), OC(═O)R_(a), C(═O)OR_(a), NR_(a)R_(b),NR_(b)C(═O)R_(a), C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(a),OC(═O)NR_(b)R_(c), and NR_(a)C(═O)NR_(b)R_(c). In some embodiments, eachoccurrence of R₇ is independently selected from the group consisting ofalkyl, alkenyl, cycloalkyl, optionally substituted aryl, and optionallysubstituted heterocycle. In some embodiments, each occurrence of R₇ isindependently H, Me, Et, Pr, i-Pr, Bu, or i-Bu. In some embodiments,each occurrence of R₇ is independently H, OH, SH, NH₂, CF₃, or OCF₃. Insome embodiments, R₇ is H.

In some embodiments, each occurrence of R₅, R₆, and R₇ is H.

In some embodiments, n₃ is 0, 1, or 2. In some embodiments, n₃ is 1. Insome embodiments, n₃ is 0.

In some embodiments, each occurrence of R_(a) is independently hydrogen,alkyl, heterocycle, or aryl. In some embodiments, each occurrence ofR_(a) is independently hydrogen or alkyl. In some embodiments, eachoccurrence of R_(a) is independently H, Me, Et, Pr, i-Pr, Bu, or i-Bu.

In some embodiments, each occurrence of R_(b) and R_(c) is independentlyhydrogen, alkyl, heterocycle, or aryl. In some embodiments, eachoccurrence of R_(b) and R_(c) is independently hydrogen or alkyl.

In other embodiments, R_(b) and R_(c) together with the nitrogen atom towhich they are bonded optionally form a heterocycle comprising 1-4heteroatoms each selected from the group consisting of N, O, and S. Inother embodiments, R_(b) and R_(c) together with the nitrogen atom towhich they are bonded form optionally substituted morpholine,piperidine, or piperazine.

In some embodiments, the compound has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R₂ is H, OH, alkyl, alkoxy, halogen, NR_(b)R_(c),CF₃, OCF₃, or CN. In some embodiments, R₂ is NH₂, OH, OMe, OEt,OCH₂CH₂CH₃, or OCH(CH₃)₂. In some embodiments, R₂ is selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, tert-butyl, F, Cl,Br, CF₃, nitro, OMe, OEt, OCF₃, —C(═O)Me, —C(═O)OMe, —NHC(═O)Me,1,4-dioxanyl, cyclohexanyl, cyclohexenyl, phenoxy, 2-methoxyphenoxy,3-methoxyphenoxy, 4-methoxyphenoxy, 2-chlorophenoxy, 3-chlorophenoxy,4-chlorophenoxy, 2-methylphenoxy, 3-methylphenoxy, and 4-methylphenoxy.In some embodiments, R₂ is OMe, OEt, OPr, OBu, or O-iBu. In someembodiments, R₂ is OMe.

In some embodiments, R₃ is H, OH, alkyl, alkoxy, or halogen. In someembodiments, R₃ is H, Me, Et, Pr, i-Pr, Bu, or i-Bu. In someembodiments, R₃ is H.

In some embodiments, R₄ is H, alkyl, OH, NH₂, alkoxy, halogen, CF₃, orCN. In some embodiments, R₄ is H, OH, or alkoxy. In some embodiments, R₄is OH. In some embodiments, R₄ is H.

In some embodiments, the compound has the structure of Formula III,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is selected from theExamples of compounds shown in Table 1a, or a pharmaceuticallyacceptable salt thereof. The enumerated compounds in Table 1a arerepresentative and non-limiting examples of compounds of Formula I.

TABLE 1a Selected compound of Formula I, where n₁, n₂, and n₃ areindependently 1 or 2. Exam- ple No. R₁ R₂ R₃ R₄ R₅ R₆ R₇ 100 H Cl H H HF F 102 F H F H F OH Cl 103 Cl

Cl OH Cl OH NO₂ 104 CN OH CN OH Br OMe OCF₃ 105 NO₂ OMe CF₃ OH NO₂ NH₂SH 106 CF₃ OEt Me OMe OCF₃ NH₂ SH 107 OCF₃ OPr Et NH₂ OCF₃ SCH₃ OH 108OH OBu Pr NH₂ SH COOH CONH₂ 109 OH NH₂ Bu NH₂ SH COOH CONH₂ 110 SH SHCyclopropyl SH OH Ph OH 111 COOH Me H SCH₃ OH pyridinyl OH 112 COOMeCONH₂ H COOH CONH₂ Ph OH 113 CONH₂ NH(C═O)Me —CH═CH₂ COOH CONH₂ Me H 114CONMe₂ cyclopropyl Ph OH CONH₂ Et H 115 NH(C═O)Me Ph pyridinyl OHNH(C═O)Me Pr Me 116 Me 3-fluorophenyl Me OH Me cyclobutyl Et 117 Ph4-pyridinyl H NHMe Et CF₃ cyclopropyl 118 4-chlorophenyl NO₂ H NHMecyclobutyl OCF₃ NO₂ 119

CF₃ H NMe₂ 4-chlorophenyl SH pyridinyl 120 cyclobutyl OH H

Ph Ph 4-pyridinyl 121 4-pyridinyl SH H

OEt 4-chloro- phenyl CONMe₂ 122 OEt Me Me Me OPr OPr NH(CO)Me 123 OPr EtPh Me

124 OBu Pr Ph Et

In some embodiments, the compound of Formula II is selected from theExamples of compounds shown in Table 1b, or a pharmaceuticallyacceptable salt thereof. The enumerated compounds in Table 1b arerepresentative and non-limiting examples of compounds of Formula II.

TABLE 1b Selected compound of Formula II. Example No. R₂ R₃ R₄ 125 Cl HH 126 H F OH 127

Cl OH 128 OH H OH 129 OMe CF₃ OH 130 OEt Me OMe 131 OPr Et NH₂ 132 OBuPr NH₂ 133 NH₂ Bu NH₂ 134 SH cyclopropyl SH 135 Me H SCH₃ 136 CONH₂ HCOOH 137 NH(C═O)Me —CH═CH₂ COOH 138 cyclopropyl Ph OH 139 Ph pyridinylOH 140 3-fluorophenyl Me OH 141 4-pyridinyl H NHMe 142 NO₂ H NHMe 143CF₃ H NMe₂ 144 OH H

145 SH H

146 Me Me Me 147 Et Ph Me 148 Pr Ph Et

Methods of Preparation Abbreviations

-   -   ACN Acetonitrile    -   EA Ethyl acetate    -   DMF Dimethyl formamide    -   PE Petroleum ether    -   DCM Dichloromethane    -   THF Tetrahydrofuran    -   HOBT 1-Hydroxybenzotriazole    -   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HATU        N-[(dimethylamino)(3H-1,2,3-triazolelo(4,4-b)pyridin-3-yloxy)methylene]-N-methylmethaneaminium        hexafluorophosphate    -   PyBOP        1H-Benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate    -   BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride    -   BOP Benzotriazol-1-yloxytris(diethylamino)phosphonium        hexafluorophosphate    -   TEA Triethylamine    -   DIPEA Diisopropylethylamine    -   DMAP 4-Dimethylaminopyridine    -   PCC Pyridinium chlorochromate    -   PDC Pyridinium dichromate    -   NBS N-bromosuccinimide    -   NCS N-chlorosuccinimide    -   NIS N-iodosuccinimide    -   9-BBN 9-Borabicyclo[3.3.1]nonane    -   TsOH p-Toluenesulfonic acid    -   TFA Trifluoroacetamide    -   CDI Carbonyldiimidazole

Following are general synthetic schemes for manufacturing compounds ofthe present invention. These schemes are illustrative and are not meantto limit the possible techniques one skilled in the art may use tomanufacture the compounds disclosed herein. Different methods will beevident to those skilled in the art. Additionally, the various steps inthe synthesis may be performed in an alternate sequence or order to givethe desired compound(s). The following reactions are illustrations butnot limitations of the preparation of some of the starting materials andcompounds disclosed herein.

Schemes 1-4 below describe which may be used for the synthesis ofcompounds having the structure of Formula I, where R₁, R₂, R₃, R₄, R₅,R₆, R₇, n₁, n₂, and n₃ are defined according to any one of theembodiments disclosed herein. Because compounds of Formulae II and IIIare encompassed by Formula I, these compounds can be prepared using thesame methods described in Schemes 1-4. Various modifications to thesemethods may be envisioned by those skilled in the art to achieve similarresults given below. The starting materials and reagents used in themethod described in Schemes 1-4 are commercially available or can beprepared by methods known in the art. The reactions described in Schemes1-4 may be carried out at low temperature (e.g., 0° C.), roomtemperature, or under heating conditions (e.g., at 50, 60, 70, 80, 90 or100° C. or at the refluxing temperature of the solvent used).

In certain embodiments, as shown in Scheme 1, Step a, aminonaphthelene Xis reacted with phenulsulfonyl chloride XI to afford sulfonamide XII.Other than aminonaphthelene X, any salt of aminonaphthelene X can beused as starting material as well. Non-limiting examples of the saltsinclude HCl, H₂SO₄, HNO₃, or HAc salt or any other salts known in theart. Any suitable base, organic or inorganic, may be used in step a.Non-limiting examples of suitable bases include CH₃COONa, Na₂CO₃, K₂CO₃,NaOH, KOH, CsOH, sodium hydride, potassium carbonate, triethylamine, anddiisopropylethylamine. Non-limiting example of suitable solvents forthis reaction include DMSO, ethanol, water, THF, methylene chloride,acetonitrile, chloroform, or toluene.

In certain embodiments, as shown in Step b in Scheme 2, the obtainedsulfonamide XII is oxidized using one or more oxidation agents to affordiminonaphthalenone XIII. Non-limiting examples of suitable oxidationagents for this reaction include NaIO₄, H₂O₂, and MCPBA. Non-limitingexamples of suitable solvents for this reaction include DMSO, ethanol,water, THF, methylene chloride, acetonitrile, chloroform, or toluene.

In certain embodiments, as shown in Step c in Scheme 3, the obtainediminonaphthalenone XIII is coupled with naphthalene XIV to affordcompound of Formula Ix. One or more lewis acids may be used tofacilitate this coupling reaction. Non-limiting examples of suitablelewis acids for this reaction include BF₃, FeCl₂, FeCl₃, CuCl₂, andAlCl₃. Non-limiting examples of suitable solvents for this reactioninclude DMSO, ethanol, water, THF, methylene chloride, acetonitrile,chloroform, and toluene.

In certain embodiments, as shown in Step d in Scheme 4, the obtainedcompound of Formula Ix is oxidized using one or more oxidation agents toafford compound of Formula I. Non-limiting examples of suitableoxidation agents for this reaction include NaIO₄, H₂O₂, and MCPBA.Non-limiting examples of suitable solvents for this reaction includeDMSO, ethanol, water, THF, methylene chloride, acetonitrile, chloroform,or toluene.

Thus, in yet another aspect, a method of making a compound of Formula Iis disclosed, including the step of oxidizing a compound of Formula Ixto form the compound of Formula I using an oxidation reagent in step a):

-   -   where each occurrence of R₁ is independently hydrogen, halogen,        cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₁ is 0, 1, 2, 3, or 4;    -   each occurrence of R₂ is independently hydrogen, halogen, cyano,        nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a),        C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c),        NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c),        alkyl, alkenyl, cycloalkyl, cycloalkenyl, optionally substituted        aryl, optionally substituted aryloxyl, or optionally substituted        heterocycle;    -   n₂ is 0, 1, 2, 3, 4, or 5;    -   R₃ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), OC(═O)R_(a), alkyl, alkenyl, cycloalkyl, or optionally        substituted aryl or heteroaryl;    -   R₄ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),        SR_(a), NR_(b)R_(c), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl;    -   each occurrence of R₅, R₆, and R₇ is independently hydrogen,        halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),        OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),        C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),        NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, optionally        substituted aryl, or optionally substituted heterocycle;    -   n₃ is 0, 1, 2, 3, or 4; and    -   each occurrence of R_(a), R_(b), and R_(c) is independently        hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,        heterocycle, or aryl; or said R_(b) and R_(c) together with the        nitrogen atom to which they are bonded optionally form a        heterocycle comprising 1-4 heteroatoms.

In some embodiments, the oxidation reagent is selected from the groupconsisting of NaIO₄, H₂O₂, MCPBA, and a combination thereof. In somespecific embodiments, the oxidation reagent is NaIO₄. In someembodiments, NaIO₄ is prepared in situ.

In some embodiments, the oxidation reagent is used in the amount ofabout 1.5-4.0 equivalence to the compound of Formula Ix. In someembodiments, the oxidation reagent is used in the amount of about 1.5,2.0, 2.5, 3.0, 3.5, or 4.0 equivalence to the compound of Formula Ix, orin an equivalence in an range bounded by any two values disclosedherein.

In some embodiments, the oxidation reagent is used in the amount ofabout 2.0-3.5 equivalence to the compound of Formula Ix. In someembodiments, the oxidation reagent is used in the amount of about 2.5equivalence to the compound of Formula Ix.

In some embodiments, step a is conducted for about 12 hours to about 2days. In any one or more of the embodiments described herein, step a isconducted for about 1 day.

In some embodiments, each occurrence of R₁ is independently hydrogen,halogen, cyano, nitro, CF₃, OCF₃, OR_(a), or SR_(a).

In some embodiments, each occurrence of R₁ is H.

In some embodiments, each occurrence of R₂ is independently halogen,cyano, nitro, CF₃, OCF₃, OR_(a), or SR_(a).

In some embodiments, R₂ is OMe and n₂ is 1.

In some embodiments, R₃ is OCF₃, OR_(a), SR_(a), OC(═O)R_(a), alkyl,alkenyl, or cycloalkyl. In some embodiments, R₃ is H.

In any one or more of the embodiments described herein, the compound ofFormula I has the structure of Formula III,

and the compound of Formula Ix has the structure of Formula IIIx,

Methods of Inhibiting STAT3 and Treatment of a Disorder

In yet another aspect, a method of inhibiting STAT3 in a cell isdescribed, comprising delivering to the cell an effective amount of atleast one compound according to any one or more of the embodimentsdescribed herein or a pharmaceutically acceptable salt thereof.

In some embodiments, the cell is in vivo in a mammal. In someembodiments, the mammal is a human, a dog, a cat, a horse, a cow, a pig,a sheep, goat, or a Tasmanian devil. In some embodiments, the mammal isa human.

In some embodiments, the cell is a cancer cell. In some embodiments, themethod further includes inducing apoptosis in the cancer cell. In someembodiments, the method further includes inhibiting angiogenesis in atumor, enhancing anti-tumor immune-mediated cytotoxicity, decreasingtumor growth, improving the mammal's survival, inhibiting STAT3phosphorylation, and/or inhibiting nuclear-to-cytoplasmic translocationof STAT3.

In some embodiments, the human is suffering from, or known, suspected,or at risk for developing anaphylaxis, muscle wasting, muscle weakness,cachexia, asthma, ulcerative colitis, non-alcoholic fatty liver disease,fibrosis, steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis,age-related macular degeneration, amyloidosis,astrogliosis due to Alzheimer's or other neurodegenerative disease, or acombination thereof.

In some embodiments, the hyperproliferative disease is selected from thegroup consisting of head and neck cancer, lung cancer, liver cancer,breast cancer, skin cancer, kidney cancer, testicular cancer, coloncancer, rectal cancer, gastric cancer, metastatic melanoma, prostatecancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer,gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer,anal cancer, prostate cancer, multiple myeloma, post-transplantlymphoproliferative disease, restenosis, myelodysplastic syndrome, andleukemia. In some embodiments, the leukemia is acute myelogenousleukemia.

In some embodiments, the fibrosis is selected from the group consistingof pulmonary fibrosis, bone marrow fibrosis, intestine fibrosis,pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperionteum,myelofibrosis, and dermal fibrosis.

In some embodiments, the viral infection is a chronic viral infection.In some embodiments, the chronic viral infection is AIDS, HIV infection,Hepatitis B virus infection, Hepatitis C virus infection, orEpstein-Barr virus infection.

In some embodiments, the disorder is asthma, psoriasis, inflammatorybowel disease, uveitis, scleritis, multiple sclerosis, graft-versus-hostdiseases, pancreatitis, pulmonary lymphangioleiomyomatosis, age-relatedmacular degeneration, or amyloidosis. In some embodiments, theanaphylaxis comprises anaphylactic shock.

In some embodiments, the disorder is selected from the group consistingof muscle wasting, muscle weakness, cachexia, and a combination thereof;and the human has or is at risk of having muscle wasting, cachexia,renal failure, cancer, AIDS, HIV infection, chronic obstructive lungdisease (including emphysema), multiple sclerosis, congestive heartfailure, tuberculosis, familial amyloid polyneuropathy, acrodynia,hormonal deficiency, metabolic acidosis, infectious disease, chronicpancreatitis, autoimmune disorder, celiac disease, Crohn's disease,electrolyte imbalance, Addison's disease, sepsis, burns, trauma, fever,long bone fracture, hyperthyroidism, prolonged steroid therapy, surgery,bone marrow transplant, atypical pneumonia, brucellosis, endocarditis,Hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome,polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus,visceral leishmaniasis, prolonged bed rest, or drug addiction. In someembodiments, the chronic obstructive lung disease is emphysema.

In yet another aspect, a method of treating or preventing a disorder ina mammalian species in need thereof is described, comprisingadministering to the mammalian species a therapeutically effectiveamount of at least one compound according to any one or more embodimentsdescribed herein or a pharmaceutically acceptable salt thereof, whereinthe disorder is selected from the group consisting of aneurodegenerative disease, anaphylaxis, muscle wasting, muscle weakness,cachexia, asthma, ulcerative colitis, non-alcoholic fatty liver disease,fibrosis, steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, amyloidosis,and a combination thereof.

In some embodiments, the mammalian species is a human, a dog, a cat, ahorse, a cow, a pig, a sheep, or a goat. In some embodiments, themammalian species is a human. In some embodiments, the human issuffering from, at risk of having, or susceptible to have a disorder.

In any one or more of the embodiments described herein, the disorder isselected from the group consisting of a neurodegenerative disease,anaphylaxis, muscle wasting, muscle weakness, cachexia, asthma,ulcerative colitis, non-alcoholic fatty liver disease, fibrosis,steatohepatitis, chagasic cardiomyopathy, scleroderma, ahyperproliferative disease, a viral infection, myelodysplastic syndrome,asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis,multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonarylymphangioleiomyomatosis, age-related macular degeneration, amyloidosis,and a combination thereof. In some embodiments, the neurodegenerativedisease is chemotherapy-induced peripheral neuropathy, diabeticneuropathy or chemobrain.

Assays for Effectiveness

STAT3 cellular inhibition can be assayed using PY-Stat3 antibodies tomeasure PY-stat3 analyze in lysates of cells by luminex beads,immunoblotting, or eliza or in slides of tissue by immunohistochemistryin peripheral blood mononuclear cell and tumor cell lines (kasumi-1) intumor samples.

The invention will now be further described by the working examplesbelow, which are preferred embodiments of the invention. These examplesare illustrative rather than limiting, and it is to be understood thatthere may be other embodiments that fall within the spirit and scope ofthe invention as defined by the claims appended hereto.

Pharmaceutical Compositions

This invention also provides a pharmaceutical composition comprising atleast one of the compounds as described herein or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

In yet another aspect, a pharmaceutical composition is described,comprising at least one compound according to any one or more of theembodiments described herein, e.g., compounds of Formula I, II, or III,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial, involved in carrying or transporting the subjectpharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically acceptable carriers include: sugars, such aslactose, glucose, and sucrose; starches, such as corn starch and potatostarch; cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients, such as cocoa butter and suppositorywaxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil, and soybean oil; glycols, such as butyleneglycol; polyols, such as glycerin, sorbitol, mannitol, and polyethyleneglycol; esters, such as ethyl oleate and ethyl laurate; agar; bufferingagents, such as magnesium hydroxide and aluminum hydroxide; alginicacid; pyrogen-free water; isotonic saline; Ringer's solution; ethylalcohol; phosphate buffer solutions; and other non-toxic compatiblesubstances employed in pharmaceutical formulations. The term “carrier”denotes an organic or inorganic ingredient, natural or synthetic, withwhich the active ingredient is combined to facilitate the application.The components of the pharmaceutical compositions also are capable ofbeing comingled with the compounds of the present invention, and witheach other, in a manner such that there is no interaction which wouldsubstantially impair the desired pharmaceutical efficiency.

As set out above, certain embodiments of the present pharmaceuticalagents may be provided in the form of pharmaceutically acceptable salts.The term “pharmaceutically acceptable salt,” in this respect, refers tothe relatively non-toxic, inorganic, and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound of theinvention in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed. Representative salts includethe hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, napthylate, mesylate, glucoheptonate, lactobionate,laurylsulphonate salts, and the like. (See, for example, Berge et al.,(1977) “Pharmaceutical Salts,”, J. Pharm. Sci. 66:1-19.)

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, butionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups, and thus are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptablebases. The term “pharmaceutically acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic, and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate, orbicarbonate of a pharmaceutically acceptable metal cation, with ammonia,or with a pharmaceutically acceptable organic primary, secondary, ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, aluminum salts, andthe like. Representative organic amines useful for the formation of baseaddition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like. (See, forexample, Berge et al., supra.)

Wetting agents, emulsifiers, and lubricants, such as sodium laurylsulfate, magnesium stearate, and polyethylene oxide-polybutylene oxidecopolymer, as well as coloring agents, release agents, coating agents,sweetening, flavoring and perfuming agents, preservatives, andantioxidants can also be present in the compositions.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal,and/or parenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated and the particular mode ofadministration. The amount of active ingredient, which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of 100%, this amount will range from about 1% to about99% of active ingredient, preferably from about 5% to about 70%, mostpreferably from about 10% to about 30%.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely-divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouthwashes and the like,each containing a predetermined amount of a compound of the presentinvention as an active ingredient. A compound of the present inventionmay also be administered as a bolus, electuary, or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, and the like),the active ingredient is mixed with one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, suchas, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; humectants, such as glycerol;disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, sodium carbonate, andsodium starch glycolate; solution-retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as, for example, cetyl alcohol, glycerol monostearate, andpolyethylene oxide-polybutylene oxide copolymer; absorbents, such askaolin and bentonite clay; lubricants, such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof; and coloring agents. In the case of capsules,tablets, and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxybutylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active, or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pills,and granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well-known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxybutylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes, and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions, which canbe dissolved in sterile water or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a compositions that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups, and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isobutylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, butylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof. Additionally, cyclodextrins,e.g., hydroxybutyl-β-cyclodextrin, may be used to solubilize compounds.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax, or a salicylate, and which is solid at roomtemperature, but liquid at body temperature and therefore, will melt inthe rectum or vaginal cavity and release the active pharmaceuticalagents of the invention.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams, or spray formulations containing such carriers as are known inthe art to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches, and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams, and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc, and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates, and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the pharmaceutical agentsin the proper medium. Absorption enhancers can also be used to increasethe flux of the pharmaceutical agents of the invention across the skin.The rate of such flux can be controlled by either providing a ratecontrolling membrane or dispersing the compound in a polymer matrix orgel.

Ophthalmic formulations, eye ointments, powders, solutions, and thelike, are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient, orsuspending or thickening agents.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. One strategy for depot injections includes the use ofpolyethylene oxide-polypropylene oxide copolymers wherein the vehicle isfluid at room temperature and solidifies at body temperature.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly (orthoesters) and poly (anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions, which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably, 0.5% to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The compounds and pharmaceutical compositions of the present inventioncan be employed in combination therapies, that is, the compounds andpharmaceutical compositions can be administered concurrently with, priorto, or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, the compound of the present invention may beadministered concurrently with another anti-inflammatory orimmunosupressant agent); such as but not limited to NSAIDS, DMARDS,steroids, or biologics such as antibody therapies), or they may achievedifferent effects (e.g., control of any adverse effects).

The compounds of the invention may be administered intravenously,intramuscularly, intraperitoneally, subcutaneously, topically, orally,or by other acceptable means. The compounds may be used to treatarthritic conditions in mammals (e.g., humans, livestock, and domesticanimals), race horses, birds, lizards, and any other organism which cantolerate the compounds.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use, or sale for human administration.

Administration to a Subject

Some aspects of the invention involve administering an effective amountof a composition to a subject to achieve a specific outcome. Thesmall-molecule compositions useful according to the methods of thepresent invention thus can be formulated in any manner suitable forpharmaceutical use.

The formulations of the invention are administered in pharmaceuticallyacceptable solutions which may routinely contain pharmaceuticallyacceptable concentrations of salt, buffering agents, preservatives,compatible carriers, adjuvants, and optionally other therapeuticingredients.

For use in therapy, an effective amount of the compound can beadministered to a subject by any mode allowing the compound to be takenup by the appropriate target cells. “Administering” the pharmaceuticalcomposition of the present invention can be accomplished by any meansknown to the skilled artisan. Specific routes of administration includebut are not limited to oral, transdermal (e.g., via a patch), parenteralinjection (subcutaneous, intradermal, intramuscular, intravenous,intraperitoneal, intrathecal, etc.), or mucosal (intranasal,intratracheal, inhalation, intrarectal, intravaginal, etc.). Aninjection can be in a bolus or a continuous infusion.

For example the pharmaceutical compositions according to the inventionare often administered by intravenous, intramuscular, or otherparenteral means. They can also be administered by intranasalapplication, inhalation, topically, orally, or as implants, and evenrectal or vaginal use is possible. Suitable liquid or solidpharmaceutical preparation forms are, for example, aqueous or salinesolutions for injection or inhalation, microencapsulated, encochleated,coated onto microscopic gold particles, contained in liposomes,nebulized, aerosols, pellets for implantation into the skin, or driedonto a sharp object to be scratched into the skin. The pharmaceuticalcompositions also include granules, powders, tablets, coated tablets,(micro)capsules, suppositories, syrups, emulsions, suspensions, creams,drops, or preparations with protracted release of active compounds, inwhose preparation excipients and additives and/or auxiliaries such asdisintegrants, binders, coating agents, swelling agents, lubricants,flavorings, sweeteners, or solubilizers are customarily used asdescribed above. The pharmaceutical compositions are suitable for use ina variety of drug delivery systems. For a brief review of presentmethods for drug delivery, see Langer R (1990) Science 249:1527-33,which is incorporated herein by reference.

The concentration of compounds included in compositions used in themethods of the invention can range from about 1 nM to about 100 μM.Effective doses are believed to range from about 10 picomole/kg to about100 micromole/kg.

The pharmaceutical compositions are preferably prepared and administeredin dose units. Liquid dose units are vials or ampoules for injection orother parenteral administration. Solid dose units are tablets, capsules,powders, and suppositories. For treatment of a patient, depending onactivity of the compound, manner of administration, purpose of theadministration (i.e., prophylactic or therapeutic), nature and severityof the disorder, age, and body weight of the patient, different dosesmay be necessary. The administration of a given dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units. Repeated and multiple administration ofdoses at specific intervals of days, weeks, or months apart are alsocontemplated by the invention.

The compositions can be administered per se (neat) or in the form of apharmaceutically acceptable salt. When used in medicine, the saltsshould be pharmaceutically acceptable, but non-pharmaceuticallyacceptable salts can conveniently be used to prepare pharmaceuticallyacceptable salts thereof. Such salts include, but are not limited to,those prepared from the following acids: hydrochloric, hydrobromic,sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulphonic, tartaric, citric, methane sulphonic, formic, malonic,succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, suchsalts can be prepared as alkaline metal or alkaline earth salts, such assodium, potassium, or calcium salts of the carboxylic acid group.

Suitable buffering agents include: acetic acid and a salt (1-2% w/v);citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v);and phosphoric acid and a salt (0.8-2% w/v). Suitable preservativesinclude benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9%w/v); parabens (0.01-0.25% w/v); and thimerosal (0.004-0.02% w/v).

Compositions suitable for parenteral administration conveniently includesterile aqueous preparations, which can be isotonic with the blood ofthe recipient. Among the acceptable vehicles and solvents are water,Ringer's solution, phosphate buffered saline, and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed mineral or non-mineral oil may be employed, including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid finduse in the preparation of injectables. Carrier formulations suitable forsubcutaneous, intramuscular, intraperitoneal, intravenous, etc.administrations can be found in Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa.

The compounds useful in the invention can be delivered in mixtures ofmore than two such compounds. A mixture can further include one or moreadjuvants in addition to the combination of compounds.

A variety of administration routes is available. The particular modeselected will depend, of course, upon the particular compound selected,the age and general health status of the subject, the particularcondition being treated, and the dosage required for therapeuticefficacy. The methods of this invention, generally speaking, can bepracticed using any mode of administration that is medically acceptable,meaning any mode that produces effective levels of response withoutcausing clinically unacceptable adverse effects. Preferred modes ofadministration are discussed above.

The compositions can conveniently be presented in unit dosage form andcan be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the compounds into associationwith a carrier which constitutes one or more accessory ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelybringing the compounds into association with a liquid carrier, a finelydivided solid carrier, or both, and then, if necessary, shaping theproduct.

Other delivery systems can include time-release, delayed-release, orsustained-release delivery systems. Such systems can avoid repeatedadministrations of the compounds, increasing convenience to the subjectand the physician. Many types of release delivery systems are availableand known to those of ordinary skill in the art. They include polymerbase systems such as poly(lactide-glycolide), copolyoxalates,polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyricacid, and polyanhydrides. Microcapsules of the foregoing polymerscontaining drugs are described in, for example, U.S. Pat. No. 5,075,109.Delivery systems also include non-polymer systems that are: lipidsincluding sterols such as cholesterol, cholesterol esters, and fattyacids or neutral fats such as mono-, di- and triglycerides; hydrogelrelease systems; silastic systems; peptide-based systems; wax coatings;compressed tablets using conventional binders and excipients; partiallyfused implants; and the like. Specific examples include, but are notlimited to: (a) erosional systems in which an agent of the invention iscontained in a form within a matrix such as those described in U.S. Pat.Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems inwhich an active component permeates at a controlled rate from a polymersuch as described in U.S. Pat. Nos. 3,854,480, 5,133,974, and 5,407,686.In addition, pump-based hardware delivery systems can be used, some ofwhich are adapted for implantation.

EQUIVALENTS

The representative examples which follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that the contents ofthose cited references are incorporated herein by reference to helpillustrate the state of the art. The following examples containimportant additional information, exemplification, and guidance whichcan be adapted to the practice of this invention in its variousembodiments and equivalents thereof.

EXAMPLES Example 1. Synthesis of Compound Formula III and Compound ofFormula IIIx Step 1: Formation of Sulfonamido-Naphthol

Step 1 is the reaction of 4-methoxybenzenesulfonyl chloride (1) and4-amino-1-napthol HCl (2) in the presence of sodium acetate to affordsulfonamido-naphthol (3). To a 5 L round bottom flask with mechanicalstirring was added 2 (139.19 g, 694 mmol) and water (2.0 L). To thestirred suspension was added sodium acetate (176.12 g, 2.13 mol) and 1(177.52 g, 816 mmol) using an additional water heel (800 mL). Thereaction was heated to 85° C. via electric mantel and the temperaturemonitored with calibrated thermocouple. The reaction was monitored byTLC and cooled after 2 h at the set temperature. The purple precipitateformed during the reaction was filtered, washed with water (1400 mL inportions), and dried in a heated (55° C.) vacuum oven for 18 h under anitrogen purge. The purple intermediate 3 (223.78 g, 95% yield) wascharacterized by 1H NMR and LCMS.

Step 2: Formation of Sulfonyl-Iminoquinone

Step 2 is the oxidation of sulfonamido-naphthol (3) with sodiumperiodate on silica in the presence of dichloromethane (DCM) to affordsulfonyl-iminoquinone (4). Specifically, sodium periodate on silica wasgenerated in situ by combining sodium periodate in water. A 20 L,round-bottom flask was charged with water (370 mL) and heated to 90° C.Sodium periodate (157.7 g, 737 mmol) was added with stirring and allowedto dissolve. This solution was applied by vacuum to a 20 L flaskcontaining silica gel (624.8 g). The resulting free-flowing solids wereused as is in the next step.

Intermediate 3 (120.3 g, 365 mmol) was added to a 5 L, round-bottomflask with mechanical stirring. Dichloromethane (DCM, 3 L) was added andmechanical stirring begun. To the slurry was charged the sodiumperiodate/silica (280.6 g, 183 mmol). The brown/yellow mixture wasstirred at room temperature for 60 min, at which time TLC indicatedconsumption of starting material. Sodium sulfate (101 g) was added toact as a drying agent prior to filtration. The reaction was filtered andwashed with DCM (680 mL), and the solution of formed intermediate 4 wastransferred to a clean 5 L reactor.

Step 3: Formation of Compound of Formula IIIx

Step 3 is the in situ condensation of the sulfonyl-iminoquinone (4) with2-napthol (5) in the presence of dichloromethane (DCM) and catalyticboron trifluoride etherate to afford compound of Formula IIIx. Thesolution was blanketed with nitrogen and stirred, and 5 (52.7 g, 365mmol) was added. Boron trifluoride etherate (2.1 mL, 17.5 mmol) wasadded, and the reaction was heated to 35° C. A second portion of thesame quantity was added 15 min later. The reaction was stirred for 2 h,and was then filtered over a coarse frit after cooling. The product waswashed with DCM (300 mL portions) in two portions. The crude product(IIIx, 154.2 g) was dried in a heated (55° C.) vacuum oven for 60 hunder a nitrogen purge.

The crude compound IIIx was added to a 5 L flask with absolute ethanol(1.5 L), and heated to 35° C. for 3 h. The slurry was then filtered andwashed with ethanol (150 mL). The solids were dried in a heated (55° C.)vacuum oven for 24 h under a nitrogen purge. The product IIIx (143.5 g,83% yield) was characterized by 1H NMR and LC-MS.

Step 4: Formation of Compound of Formula III

A 500 mL, one neck flask, fitted with a stopper and magnetic stir bar,was charged with compound of Formula IIIx (8.30 g, 17.6 mmol) andacetone (87 mL). To the resulting solution was added NaIO₄/SiO₂ (13.69g, 8.80 mmol) in one portion and the mixture was stirred at ambienttemperature for 20 h. The color of the reaction mixture turned from pinkto dark red. Analysis by TLC (1/1 hexane:acetone, UV 254 nm) showed somecompound of Formula IIIx remaining. More NaIO₄/SiO₂ (13.7 g, 8.8 mmol)was added and the mixture was stirred at ambient temperature for 24 h.Analysis by TLC showed some compound of Formula IIIx remaining. Thereaction mixture was filtered and the filtrate was charged with moreNaIO₄/SiO₂ (13.7 g, 8.8 mmol). The mixture was stirred at ambienttemperature for 6 h. Analysis by TLC showed some compound of FormulaIIIx remaining. More NaIO₄/SiO₂ (13.7 g, 8.8 mmol) was added and themixture was stirred at ambient temperature for 22 h. Analysis by TLCshowed some compound of Formula IIIx remaining. The reaction mixture wasfiltered and more NaIO₄/SiO₂ (13.7 g, 8.8 mmol) was added to thefiltrate. The mixture was stirred at ambient temperature for 24 h.Analysis by LC-MS showed 76% conversion to compound of Formula III. Themixture continued to stir at ambient temperature for 20 h. The reactionmixture was filtered and the flask and solids were washed with acetone.Approximately half of the filtrate was concentrated and purified bynormal phase silica gel (80 g of silica, gradient 0 to 60% acetone inhexanes) to give compound of Formula III (2.3 g). IR spectrum ofcompound of Formula III is depicted in FIG. 1.

Example 5. STAT3 Inhibition IC₅₀ of Compound of Formula IIIx andCompound Formula III

The following compounds were tested for their ability to block STAT3binding to its phosphopeptide ligand in a surface plasmon resonance(SPR)-based binding assay and to inhibit IL-6-mediated phosphorylationof STAT1, STAT3, and STAT5. Inhibition of nuclear translocation ofphosphorylated STAT3 was also tested. The IC₅₀ (μM) values are shown inTable 2. More details of these assays are described in U.S. Pat. No.8,779,001; Haricharan et al., Mechanism and preclinical prevention ofincreased breast cancer risk caused by pregnancy, Cell biology: Humanbiology and medicine, 2013, 1-24; the entire contents of which areincorporated by reference.

TABLE 2 IC₅₀ (μM) values of compound of Formula III CompoundPhosphorylation formula structure SPR pSTAT1 pSTAT3 pSTAT5 TranslocFormula III

2.3 2.2 3.0 1.8 18 Formula IIIx

2.5 3.7 2.8 4.1 50

The invention claimed is:
 1. A pharmaceutical composition, comprising(a) a compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein each occurrenceof R₁ is independently hydrogen, halogen, cyano, nitro, CF₃, OCF₃,OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c),NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl,optionally substituted aryl, or optionally substituted heterocycle; n₁is 0, 1, 2, 3, or 4; each occurrence of R₂ is independently hydrogen,halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a),OC(═O)R_(a), C(═O)OR_(a), NR_(b)R_(c), NR_(b)C(═O)R_(c),C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c), OC(═O)NR_(b)R_(c),NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl, cycloalkenyl,optionally substituted aryl, optionally substituted aryloxyl, oroptionally substituted heterocycle; n₂ is 0, 1, 2, 3, 4, or 5; R₃ ishydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a), SR_(a), OC(═O)R_(a),alkyl, alkenyl, cycloalkyl, or optionally substituted aryl orheteroaryl; R₄ is hydrogen, halogen, cyano, nitro, CF₃, OCF₃, OR_(a),SR_(a), NR_(b)R_(c), OC(═O)R_(a), alkyl, alkenyl, or cycloalkyl; eachoccurrence of R₅, R₆, and R₇ is independently hydrogen, halogen, cyano,nitro, CF₃, OCF₃, OR_(a), SR_(a), C(═O)R_(a), OC(═O)R_(a), C(═O)OR_(a),NR_(b)R_(c), NR_(b)C(═O)R_(c), C(═O)NR_(b)R_(c), NR_(b)C(═O)OR_(c),OC(═O)NR_(b)R_(c), NR_(a)C(═O)NR_(b)R_(c), alkyl, alkenyl, cycloalkyl,optionally substituted aryl, or optionally substituted heterocycle; n₃is 0, 1, 2, 3, or 4; and each occurrence of R_(a), R_(b), and R_(c) isindependently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle, or aryl; or said R_(b) and R_(c) together with thenitrogen atom to which they are bonded optionally form a heterocyclecomprising 1-4 heteroatoms; and (b) a pharmaceutically acceptableexcipient.
 2. The pharmaceutical composition of claim 1, wherein eachoccurrence of R₁ is independently hydrogen, halogen, cyano, nitro, CF₃,OCF₃, OR_(a), or SR_(a).
 3. The pharmaceutical composition of claim 1,wherein n₁ is 0, 1, or
 2. 4. The pharmaceutical composition of claim 1,wherein each occurrence of R₂ is independently hydrogen, halogen, cyano,nitro, CF₃, OCF₃, OR_(a), or SR_(a).
 5. The pharmaceutical compositionof claim 1, wherein R₃ is hydrogen, halogen, cyano, nitro, or CF₃. 6.The pharmaceutical composition of claim 1, wherein R₄ is hydrogen,halogen, cyano, nitro, or OR_(a).
 7. The pharmaceutical composition ofclaim 1, wherein R₅, R₆, and R₇ are each independently selected from thegroup consisting of hydrogen, halogen, cyano, nitro, and CF₃.
 8. Thepharmaceutical composition of claim 1 wherein the compound has thestructure of Formula II:

or a pharmaceutically acceptable salt thereof.
 9. The pharmaceuticalcomposition of claim 8, wherein R₂ is NH₂, OH, OMe, OEt, OCH₂CH₂CH₃, orOCH(CH₃)₂.
 10. The pharmaceutical composition of claim 8, wherein R₃ isH, OH, alkyl, alkoxy, or halogen.
 11. The pharmaceutical composition ofclaim 8, wherein R₄ is H, alkyl, OH, NH₂, alkoxy, halogen, CF₃, or CN.